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Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer

Englund, E LU ; Bartoschek, M LU ; Reitsma, B LU ; Jacobsson, L LU ; Escudero-Esparza, A LU ; Orimo, Akira; Leandersson, K LU ; Hagerling, C LU ; Aspberg, A LU and Storm, P LU , et al. (2016) In Oncogene 35(43). p.5585-5596
Abstract

Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdc(scid)/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected,... (More)

Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdc(scid)/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected, tumors. In vitro experiments confirmed that COMP-expressing cells had a more invasive phenotype, which could in part be attributed to an upregulation of matrix metalloprotease-9. Furthermore, microarray analyses of gene expression in tumors formed in vivo showed that COMP expression induced higher expression of genes protecting against endoplasmic reticulum stress. This observation was confirmed in vitro as COMP-expressing cells showed better survival as well as a higher rate of protein synthesis when treated with brefeldin A, compared with control cells. Further, COMP-expressing cells appeared to undergo a metabolic switch, that is, a Warburg effect. Thus, in vitro measurement of cell respiration indicated decreased mitochondrial metabolism. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by metabolic switching and increasing invasiveness and tumor cell viability, leading to reduced survival in animal models and human patients.

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Animals, Apoptosis, Biomarkers, Tumor, Breast Neoplasms, Cartilage Oligomeric Matrix Protein, Cell Adhesion, Cell Line, Cell Membrane, Cell Movement, Cell Transformation, Neoplastic, Disease Models, Animal, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Gene Expression, Gene Expression Profiling, Heterografts, Humans, Immunohistochemistry, Matrix Metalloproteinase 9, Mice, SCID, Neoplasm Metastasis, Oxidative Phosphorylation, Prognosis, Proportional Hazards Models, Recurrence, Journal Article
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Oncogene
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35
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43
pages
12 pages
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Nature Publishing Group
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  • scopus:84963626988
ISSN
1476-5594
DOI
10.1038/onc.2016.98
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English
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yes
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ee475f9a-8fab-4cbf-9d82-1bdbe6637f2d
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2017-09-11 11:52:14
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2017-10-01 05:39:36
@article{ee475f9a-8fab-4cbf-9d82-1bdbe6637f2d,
  abstract     = {<p>Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdc(scid)/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected, tumors. In vitro experiments confirmed that COMP-expressing cells had a more invasive phenotype, which could in part be attributed to an upregulation of matrix metalloprotease-9. Furthermore, microarray analyses of gene expression in tumors formed in vivo showed that COMP expression induced higher expression of genes protecting against endoplasmic reticulum stress. This observation was confirmed in vitro as COMP-expressing cells showed better survival as well as a higher rate of protein synthesis when treated with brefeldin A, compared with control cells. Further, COMP-expressing cells appeared to undergo a metabolic switch, that is, a Warburg effect. Thus, in vitro measurement of cell respiration indicated decreased mitochondrial metabolism. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by metabolic switching and increasing invasiveness and tumor cell viability, leading to reduced survival in animal models and human patients.</p>},
  author       = {Englund, E and Bartoschek, M and Reitsma, B and Jacobsson, L and Escudero-Esparza, A and Orimo, Akira and Leandersson, K and Hagerling, C and Aspberg, A and Storm, P and Okroj, M and Mulder, H and Jirström, K and Pietras, K and Blom, A M},
  issn         = {1476-5594},
  keyword      = {Animals,Apoptosis,Biomarkers, Tumor,Breast Neoplasms,Cartilage Oligomeric Matrix Protein,Cell Adhesion,Cell Line,Cell Membrane,Cell Movement,Cell Transformation, Neoplastic,Disease Models, Animal,Endoplasmic Reticulum,Endoplasmic Reticulum Stress,Female,Gene Expression,Gene Expression Profiling,Heterografts,Humans,Immunohistochemistry,Matrix Metalloproteinase 9,Mice, SCID,Neoplasm Metastasis,Oxidative Phosphorylation,Prognosis,Proportional Hazards Models,Recurrence,Journal Article},
  language     = {eng},
  number       = {43},
  pages        = {5585--5596},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer},
  url          = {http://dx.doi.org/10.1038/onc.2016.98},
  volume       = {35},
  year         = {2016},
}